The Flavr Savr Tomato

In May 1994, consumers were introduced to genetic engineering's first ready-to-eat produce: the Flavr Savr tomato. The FDA had just ruled that the two extra pieces of recombinant DNA that Calgene Inc. had manipulated into this cultivar posed no appreciable health risks, so these GM tomatoes were as safe for human consumption as their nonengineered cousins. Actually, the FDA was not obliged by law or policy to pass premarket judgment on these plants. Rather, Calgene (later purchased by Monsanto) requested the FDA tests largely because of concerns that a genetically engineered food without FDA approval might face high consumer resistance.

What were these two extra pieces of DNA, and what marketable bonuses did they give the engineered tomatoes? One gene was merely a marker or reporter that produces a protein conferring resistance to the antibiotic kanamy-cin. This gene's assayable presence in a plant allowed the Calgene scientists to know precisely when their attempts to incorporate foreign DNA into a tomato strain had succeeded. Kanamycin is taken orally by some people as an antibiotic drug. After considering the matter, the FDA concluded that the small amount of the kanamycin resistance protein that Flavr Savr tomatoes added to the human diet would not affect the clinical effectiveness of the antibiotic in our species.

The other introduced piece of DNA was the real crux of the engineering endeavor. It was a gene that confers upon ripened tomatoes a resistance to spoilage. Normally, ripe tomatoes rot quickly under the action of a specific enzyme (polygalacturonase) present in the fruit. The newly introduced gene reduced the action of that enzyme and thereby delayed the fruits' bruising and spoilage. This meant that Flavr Savr tomatoes could be vine-ripened yet shipped even long distances to arrive on grocery shelves in edible condition. In contrast, regular commercial tomatoes often are harvested green to withstand shipment to distant markets, but as consumers well know, the

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common result is a rather tasteless store-ripened fruit bearing little resemblance to the delicious vine-ripened specimens from their own gardens. Because many tomato connoisseurs are displeased with winter store-bought tomatoes, the hope was that the Flavr Savr would offer a scrumptious product year-round.

Unfortunately, the Flavr Savr tomato never became a market success and is no longer sold. Some consumers did not like the taste, and it was expensive. However, one benefit did ensue. The kind of basic research that created the Flavr Savr tomato, involving "antisense" technology, paradoxically has helped scientists better understood how genes are turned on and off inside plant tissues. These fundamental discoveries may be of great benefit to agricultural bioengineering over the longer term.

In engineering the Flavr Savr tomato, Calgene scientists purposefully cloned and inserted the polygalacturonase gene into the plant backwards—in reverse, or antisense, orientation. In general, such antisense transgenes inhibit the expression of their duplicate normal-polarity genes in plant cells, but the molecular mechanism underlying this phenomenon of cosuppression (also known as paramutation, or gene silencing through duplication) was a mystery. Maybe, for example, the messenger RNA (mRNA) molecules from the reverse-polarity transgene bind to the forward-polarity mRNAs to gum up the cellular works of protein translation. However, control experiments soon revealed that it did not really matter whether the transgene was cloned backward or forward; either way, the endogenous plant gene was silenced.

Further research showed that plant tissues somehow must know when too many copies of a gene are present, perhaps by sensing when the pool of RNA molecules is above some normal threshold. Under one plausible and intriguing model, viral infections provided the original selective impetus for plants to evolve a capacity to detect surplus RNAs and to silence the genes responsible. The idea is that cosuppression may be an evolved weapon originally used by plants to sense and then block the proliferation of RNA viruses that invade their tissues. Maybe the plant merely interprets the invasive duplicate transgene as just another attacking virus and silences it accordingly.

This hypothesis will require further evaluation, but regardless of the outcome, the history of the Flavr Savr tomato illustrates two broader points about GM plant research and its relationship to agribusiness. First, a successful commercial product is not the only yardstick by which the value of transgenic experimentation should be judged. Here, unexpected scientific understanding about gene regulation emerged from basic research into plant transgenesis. Second, such fundamental knowledge may prove useful in subsequent practical endeavors. In this case, future genetic engineering efforts will benefit from the discovery that simply adding transgenes to a plant's genome is not equivalent to adding functional capabilities to a plant.

Wherever and whenever cosuppression applies, by definition the insertion of a transgene for a particular protein (such as polygalacturonase) represses rather than augments the plant's endogenous production of that protein. Thus, when repression of an existing function is the desired goal (as in the case of the spoilage gene in tomatoes), the cosuppression phenomenon can be used to good advantage by genetic engineers. However, when the intent is to augment the action of an endogenous gene, the effect of adding a related transgene to plant cells has often proved to be counterintuitively counterproductive.

Despite the novel scientific insights that came from research on Flavr Savr tomatoes, the commercial product was a fizzle if not an embarrassment to the GM food industry. Thus, the project must be labeled a boondoggle with respect to its intended goal.